title: Antimalarial and Structural Studies of Pyridine-containing Inhibitors of 1-Deoxyxylulose-5-phosphate Reductoisomerase.
abstract: 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is a target for developing antimalarial drugs. Fosmidomycin, a potent DXR inhibitor, showed safety as well as efficacy againstP. falciparummalaria in clinical trials. Based on our previous quantitative structure activity relationship (QSAR) and crystallographic studies, several novel pyridine-containing fosmidomycin derivatives were designed, synthesized and found to be highly potent inhibitors ofP. falciparumDXR (PfDXR) having Kivalues of 1.9 - 13 nM, with the best one being ~11× more active than fosmidomycin. These compounds also potently block the proliferation of multi-drug resistantP. falciparumwith EC50values as low as 170 nM. A 2.3 Å crystal structure ofPfDXR in complex with one of the inhibitors is reported, showing the flexible loop of the protein undergoes conformational changes upon ligand binding and a hydrogen bond and favorable hydrophobic interactions between the pyridine group andPfDXR account for the enhanced activity.
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Xue
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Diao
authors.forename: Guobin
authors.initials: G
authors.lastname: Cai
authors.forename: Lisheng
authors.initials: L
authors.lastname: Deng
authors.forename: Baisong
authors.initials: B
authors.lastname: Zheng
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
keywords: 1-deoxy-D-Xylulose-5-Phosphate Reductoisomerase; X-ray protein crystallography; antimalrial activity; inhibitor design